With the recent evidence of significant disease association with HTLV-II and the high incidence of this virus among intravenous drug users (IVDUs), the overall goal of this project is expanded from an analysis of the humoral immune response to HTLV-I to include HTLV-II. Immunogenic epitopes of HTLV-I and -II will continue to be identified by the generation of human monoclonal antibodies (HMAbs). This approach already has identified three highly conserved epitopes. Two of these epitopes, designated MTA-1 and K55, bind respectively to 99% of sera from HTLV-I and -II infected IVDUs, American Indians and individuals from diverse geographical areas. In addition to the direct implications of these findings for diagnostic applications, these data provide evidence for the conservation of the immune response for immunodominant HTLV epitopes in diverse geographic populations. one of the project aims is to use these highly sensitive epitopes as part of a study to determine the consequences of HIV/HTLV coinfections. Other epitopes are actively being characterized since a panel of HMAbs to many HTLV-I structural proteins has been produced. In addition, some of the HMAbs are likely candidates to mediate viral neutralization which could lead to the identification of the virus receptor(s). Lastly, a novel alternative approach of combining expression cloning techniques and cell surface reporter gene method of measuring transcriptional transactivation is proposed to identify the gene(s) which encodes the cellular receptor(s), recognized by these viruses. The proposed studies should prove useful in the design of anti-HTLV-I and -II therapies as well as potential HTLV-I and -II vaccines.